The present invention provides for the treatment of lower urinary tract disorders such as urinary incontinence, detrusor instability and interstitial cystitis using agents that suppress norepinephrine uptake activity but do not have the undesirable side effects due to anti-cholinergic activity possessed by current treatments.
Urinary incontinence is generally defined as the involuntary loss of urine and is most common in four groups of patients including children, women, elderly, and neurologic disease patients. Detrusor instability is characterized by spasmodic bladder contractions or bladder contractions elicited by small volumes, and is often accompanied by incontinence and urinary frequency. Interstitial cystitis is an idiopathic pelvic pain syndrome which can also include detrusor instability as a component of its pathology.
Nocturnal enuresis is classified as an involuntary micturition during sleep after 5 years of age and may exist in either primary or secondary forms. The diagnosis of primary nocturnal enuresis is made if the patient has never developed voluntary control of micturition during sleep. The diagnosis of secondary nocturnal enuresis is made if the patient has had transient periods of micturition control during sleep. Nocturnal enuresis occurs in 30% of all children at 4 years of age, 10% at 6 years, 3% at 10 years and 1% at 18 years. Secondary nocturnal enuresis accounts for approximately 20-25% of the pediatric enurenic cases. Although some enuretic children also have diurnal enuresis, over 80% of the enuretic children have exclusively nocturnal enuresis.
The predominant types of incontinence in women are stress and urge incontinence. Stress incontinence is the involuntary loss of urine through an intact urethra produced during times of increased abdominal pressure such as during physical activity and coughing. This implies that the urethra cannot generate sufficient pressure for outlet resistance to compensate for increases in intrabladder pressure. This loss of urine is not accompanied by premonitory sensations of the need to void and is not related to the fullness of the bladder. Urge incontinence is the involuntary loss of urine through an intact urethra due to an increased intrabladder pressure. In contrast to stress incontinence, urge incontinence is caused by an episodic bladder contraction (detrusor instability) which exceeds the outlet resistance pressure generated by the urethra and is accompanied by a perception of urgency to void.
Stress incontinence is the most common form of incontinence in young women. In two longitudinal studies, pure stress incontinence was found to occur in 15-22% of women from ages 17-75+. The highest incidence of stress incontinence (25-30%) occurs at 25-45 years of age or during the childbearing years. Following the first child birth, the overall incidence and incidence of severe stress incontinence doubles. However, 35-50% of nulliparous women have also occasional stress incontinence. In a study of nulliparous nursing students between the ages of 17-24 years, daily stress incontinence was reported in 17% of the women. Urge incontinence occurs in approximately 10% of women from ages 17-75+ years and increases progressively with age. In addition to stress or urge incontinence, 7-14% of women from ages 17-75+years of age have characteristics of both urge and stress incontinence. The incidence of this "complex incontinence" doubles during the childbearing years and ranges from 13-28% from ages 17 to 75+ years of age.
The types of incontinence seen in the elderly include urge incontinence (detrusor instability), stress incontinence, complex incontinence (urge and stress incontinence) and total incontinence. Urge incontinence is the most common form of incontinence in the elderly men and women and is caused by abnormal neuromuscular responses of the bladder. Following urge incontinence in incidence are complex, stress, overflow and total incontinence, respectively. Stress incontinence is relatively rare in elderly men but common in women. Stress incontinence ,is caused by pelvic surgery, anatomical changes in the orientation of the bladder and urethra, decreased tone of the pelvic muscles, deterioration of the urethra following the cessation of estrogen secretion, and idiopathic decrease in the neuromuscular response of tile urethra. Overflow incontinence is due to an overfilling and distension of an areflexic bladder which exceeds the urethral resistance. Total incontinence is associated with dementia and sphincter or nerve damage.
In addition to the types of incontinence described above, urge incontinence is also associated with neurologic disorders such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. This urge incontinence caused by neurologic disorders result from bladder hyperactivity. The incidence of incontinence in multiple sclerosis patients has been estimated to be 60-90%. Urinary incontinence is among the early neurologic symptoms of Parkinson's disease patients and is frequently exacerbated by treatment with anti-Parkinson drugs.
Interstitial cystitis is a syndrome that is characterized by increases in urination frequency, urgency, suprapubic pressure and pain with bladder filling. This syndrome is not associated with infections or cytological damage. The average age at onset of this disorder is 40-50 years. The quality of life is considered to be worse than that of end stage renal disease. According to the NIH report on interstitial cystitis, there are 20,000 to 90,000 diagnosed cases of this disorder in United States and the upper boundary for undiagnosed cases is 4-5 times larger than the range of diagnosed cases. This disorder has increased in awareness in the urologic community due to the formation of the American Interstitial Cystitis Association.
The treatments for incontinence vary with the particular type. For example, with no therapy, the spontaneous cure rate for nocturnal enuresis is approximately 15% per year. The success rate for nonpharmacologic therapies such as motivational counseling, bladder exercises and enuresis alarms ranges from 25-70%. The tricyclic antidepressants have been the most effective pharmacologic agents for treating nocturnal enuresis. Imipramine is the most widely used agent; however other tricyclics such as nortriptyline, amitriptyline, and desipramine are also effective. Enuresis can be cured in over 50% of patients following treatment with imipramine and improvements can be seen in another 15-20%. A successful response to this therapy is usually seen in the first week of therapy and often after the first dose. The best results are seen in children with normal sized bladders who are occasionally continent at night. The worst results are seen in children with small bladders and in older adolescents. This therapy, however, does have toxic risks. The tricyclic anti-depressants in general, and imipramine in particular, are not approved for use in children under 5 years of age as these compounds are particularly toxic and potentially lethal in low dosage. Other pharmacologic therapies include the use of oxybutynin, antispasmotic agent that reduces uninhibited detrusor muscles contractions, and the antidiuretic agent desmopressin.
The predominant forms of therapy for incontinent women include a variety of surgical procedures that attempt to resuspend the bladder and/or reinforce the urethra; pelvic floor exercises; and pharmacologic therapies. Imipramine is effective as a single therapy in restoring continence to women with stress incontinence. The efficacy of imipramine in urge incontinence has varied along clinical studies and appears greater when used as a combination therapy with anticholinergic and antispasmotic agents.
Nonpharmacologic therapies for incontinence in the elderly include behavior modification, absorptive pads, catheterization and surgery. Pharmacologic therapies for stress incontinence are aimed at increasing internal sphincter tone through increasing alpha adrenergic receptor stimulation. The most common agents used are tricyclic antidepressants, ephedrine, and phenylpropanolamine. Estrogen is also used as a component in this therapy for women in order to reverse or reduce the deterioration of the genitoulinary tracts following cessation of estrogen secretion. Pharmacologic therapies for urge incontinence are aimed at suppressing episodic bladder contractions and includes agents such as propantheline, oxybutynin, and imipramine.
Nonpharmacologic therapies of interstitial cystitis include hydrodistension of the bladder during anesthesia and in extreme cases removal of the bladder with bladder reconstruction from segments of the bowel. Pharmacologic therapies include the use of dimethylsulfoxide or sodium pentosanpolysulfate by intravesicular administration and the use of tricyclic antidepressants, such as amitriptyline or desipramine. The intravesicular therapies are designed to desensitize the bladder wall, whereas the tricyclic antidepressants are used to alter the central thresholds for pain and alter bladder function.
Tricyclic antidepressants such as imipramine are among the most widely prescribed drugs for the treatment of incontinence in children, women, and elderly patients. Their effects are to decrease bladder pressure and decrease output resistance by increasing urethral pressure. As noted above, however, the urologic uses of imipramine and other tricyclic anti-depressants are limited by significant side effects due to their anti-cholinergic activities. In particular such side effects include dry mouth, constipation, drowsiness, tremors, dizziness, and excess sweating. Moreover, as noted above, the use of the tricyclics for the treatment of children is limited due to their potential toxicity.
Because its common use for the treatment of incontinence, imipramine has been the most fully studied agent for this utility. There have been at least five different proposed mechanisms that have been suggested as the basis for its effect for treating incontinence.
Imipramine has been demonstrated to have anticholinergic activity. In a series of in vitro studies with guinea pig bladder strips and in vivo bladder cystometrogram studies in guinea pigs, imipramine had anticholinergic, antispasmodic, and local anesthetic activity. (Noronha-Blob, et al., J. Pharm. Exp. Ther., 251,586 (1989)). Imipramine induced a 50% suppression of field stimulated and bethanechol-induced contraction in a rabbit bladder organ bath preparation. Atropine induced a 70% relaxation of bethanechol-induced contraction and a 30% inhibition of field stimulated contractions and verapamil induced a 85 and 81% inhibition of bethanechol and field stimulated contractions, respectively. (Kato, et al., J. Urol., 141, 1471 (1989)).
Imipramine was shown to block in vitro contractile responses of rabbit, dog, and human bladder strips to acetylcholine (ACH) (Labay and Boyarsky, J. Urol., 109, 385 (1973); Labay, et al., Arch. Phys. Med. Rehabil., 55, 166 (1974)). Imipramine also suppressed cholinergic contractile responses in dog bladder strips induced by bethanechol. The authors concluded that imipramine has anticholinergic effects (Benson, et al., Urology, 9, 31 (1977)). Imipramine also reduced bladder pressure responses in female dogs to pelvic nerve stimulation. The authors concluded these effects are "compatible with parasympatholytic activity". (Gregory, et al., Invest. Urol., 12, 233 (1974)). Somogyi, et al. (Society for Neurosciences Meeting-1989, Abstract #326.5) recently studied the effect of imipramine on the release of norepinephrine from rat bladder tissue in vitro and concluded that the "strong antagonistic effect on muscarinic presynaptic receptors" was an "action which very likely contributes to the therapeutic effects of the drug". Imipramine has an IC.sub.50 for displacement of tritiated-quinuclidinol benzoate (QNB) binding in bladder homogenates of 13.0 .mu.M compared to 52.0, 29.5 and 1.4 .mu.M for atropine, propantheline, and oxybutynin, respectively. (Levin, et al., J. Urol., 128, 396 (1982)). QNB is a radio-ligand for cholinergic receptors.
Imipramine has also been shown to affect calcium channel blockade. Olubadewo (Arch. Int. Pharmacodyn., 245, 84 (1980)) found that imipramine inhibited both Ca.sup.+2 and carbachol-induced contractions, which would indicate anticholinergic and calcium channel blockade effects. The authors stated that "On the basis of these evidences and literature reports, it was concluded that imipramine does not principally control enuresis through an effect on either the cholinergic or the adrenergic influence on bladder function." A decreased effectiveness of calcium to augment bethanechol-induced contraction of rabbit bladder strips was observed in the presence of imipramine. (Malkowicz, et al,, J. Urol., 138, 667 (1987)). The tricyclic antidepressants amitriptyline and desipramine suppressed the contractile response of rat urinary bladder strips to electrical stimulation. This effect was augmented in media with reduced calcium concentration and suppressed in media with elevated calcium concentration. The tricyclics also augment the effects of atropine. The author concluded that the effects of these tricyclics are related to the interference with calcium movement resulting in direct membrane relaxation and that these agents also have anticholinergic activity. (Akah, Arch. Int. Pharmacodyn., 284, 231 (1986)). Imipramine also induced a suppression of field stimulated and bethanechol-induced contraction in a rabbit bladder organ bath preparation (Kato, et al., supra).
Imipramine has also been shown to possess local anesthetic activity. In addition to the article by Noronha-Blob, et al., supra, imipramine was found to antagonize carbamylcholine and barium chloride-induced contractions of rabbit detrusor strips in vitro and to block the impulse conduction of frog sciatic nerves in vitro. Since imipramine suppressed responses in all of these models, the authors concluded that "imipramine is shown to exert appreciable noncompetitive antagonism of both carbamylcholine-induced and BaCl.sub.2 -induced detrusor spasms, as well as potent local anesthetic activity." (Fredericks, et al., Urology, 12, 487 (1978)). Imipramine was also shown to reduce in vitro contractile response to electrical stimulation. The author attributed "the powerful blocking effect of imipramine to its procaine-like action at the nerve terminals and the adjacent effector cell membrane". (Dhattiwala, J. Pharm. Pharmac., 28. 453 (1976)). Imipramine also suppressed contractile responses to barium chloride indicating that it has anti-spasmotic activity. (Benson, et al., Urology, 9, 31 (1977)). The authors state in their conclusions that "the mode of action of imipramine on the urinary bladder has been subject of much recent work and of much controversy. Many pathways have been proposed: (1) a central anti.-depressant effect, (2) a peripheral cholinergic receptor blockade, (3) a peripheral sympathomimetic effect via a cocaine-like blocking of nerve terminal reuptake of norepinephrine, and (4) a direct smooth muscle effect. . . . Our data indicate that imipramine has a musculotropic relaxant effect which is more potent than that of flavoxate. This direct effect on bladder smooth muscle distal to the cholinergic receptor site . . . may be important mechanism responsible for the urologic efficacy of the drug." Imipramine was also ,,shown to reduce dog bladder and urethral pressure responses to pelvic nerve stimulation and a variety of other stimuli. (Creed, et al., Brit. J. Urol., 54, 5 (1982)). These authors concluded that this agent "was acting selectively as a local anesthetic agent." The authors also stated that " imipramine . . . is unlikely to block uptake of biogenic amines" based upon their failure to see augmentation of responses to norepinephrine. Imipramine also induced a suppression of potassium-induced contraction of guinea pig bladder muscle strips in vitro; atropine and lidocaine were not effect at high concentration. (Noronha-Blob, et al., supra).
Imipramine has been found to inhibit norepinephrine reuptake. Imipramine potentiated the effects of hypogastric nerve stimulation on cat bladder relaxation in vivo (Shaffer, et al., Neuropharm., 18, 33 (1979)). These effects were considered to be evidence of uptake inhibition at catecholaminergic terminals at the bladder. Imipramine also enhanced the in vitro relaxation effects of norepinephrine on dog bladder muscle strips but had no effects alone. (Lipshultz, et at., Invest. Urol., 11, 182 (1973)). These results indicate that the effects of imipramine are indirect and mediated through the catecholinergic innervation of the bladder. Imipramine has also been shown to increase urethral pressure in female dogs and this effect could be suppressed by phenoxybenzamine (Khanna, et al., Urology, 6, 48 (1975)).
Imipramine has also been shown to inhibit the reuptake of serotonin (5-HT). The administration of imipramine increased the threshold for activating the bladder-spinal-bladder (vesicovesical) micturition reflex but had no effect on supraspinal reflex or myogenic activity of bladder with acute administration. The repeated administration of imipramine increased threshold for supraspinal reflex. Treatment with PCPA (a serotonin depleting agent) decreased acute treatment but not repeated treatment effects. (Maggi, et al., J. Pharm. Exp. Ther., 248, 278 (1988)).
In addition to the role of norepinephrine in lower urinary tract physiology, serotonergic neurons and receptors have also been shown to have effects on lower urinary tract function. These effects include the inhibition of detrusor contractile activity and the reflex responses to distension of the bladder wall by altering the threshold to sensory stimuli (Thor, et al., Development Brain Res., 54, 35 (1990); de Groat and Ryall, Exp. Brain Res., 3, 299 ( 1967); McMahon and Spillane, Brain Res., 234, 237 (1982)).
From the above, it is apparent that while imipramine and other tricyclic antidepressants are used to treat a variety of lower urinary tract disorders, the predominant mechanism responsible for these clinical effects remains unclear. Clearly these compounds have multiple mechanisms. However, which mechanism primarily responsible for any of the mentioned utilities is subject to continuing experimentation and discussion. Based upon such experimental evidence, B. D. Schmidtt, in a review article entitled "Nocturnal enuresis: An update on treatment" (Pediatr. Clin, N. Amer., 29, 21 (1982)), stated "The mechanism of action [of imipramine] seems to be largely its anti-cholinergic effect". H. G. Rushton, in his review entitled "Nocturnal enuresis: Epidemiology, evaluation and currently available treatment: options" (J. Pediatr., 114, 691 (1989)), stated "Imipramine has also been shown to exert peripheral anticholinergic and antispasmodic effects, as well as to have complex effect on sympathetic input to the bladder". L. M. D. Shortliffe and T. A. Stamey, in their chapter in the text Campbell's Urology entitled "Urinary incontinence in the female--Stress urinary incontinence" stated "Imipramine . . . It is a dibenzazepine derivative that has some anticholinergic activity and is useful for treating childhood enuresis. Although the drug's mechanism of stopping enuresis is unknown, it is thought to suppress abnormal detrusor contractions and potentiate urethral .alpha.-adrenergic activity".
Thus, the literature is, at best, uncertain as to the biological mechanism underlying the ability for the tricyclic antidepressants to treat incontinence. Moreover, it is clear that to the extent that any one or combination of these mechanisms may be useful for producing the end result, the compounds also have mechanisms which result in undesirable side effects. As noted above, imipramine and the other tricyclic antidepressants do possess a strong anticholinergic effect which likely results in the aforementioned side effects. Not only are such side effects annoying, but they may limit the effectiveness or even the use of such drugs. Accordingly, the need to discover drugs useful for treating incontinence without such side effects is evident.